Aggregation and deposition of amyloid β-protein (“Aβ” or “beta amyloid”) is considered to be a primary pathological event in Alzheimer's disease (AD) (1). While the longer 42-43 amino acid Aβ forms have been implicated in the formation of amyloid plaques (2-4), the aggregation state of the peptide is critical in determining its neurotoxicity. Many different forms of Aβ have been identified and characterized including fibrils, proto-fibrils, annular structures, globular structures, amorphous aggregates and various soluble oligomers (5-9). Numerous studies indicate that small oligomeric morphologies of Aβ are the primary toxic species in AD (10). These small oligomers are also called “low-n oligomers” (i.e., dimers, trimers, or tetramers).
One type of naturally occurring oligomeric Aβ species is a low-n oligomer that is SDS-stable, and inhibits long term potentiation in mammalian hippocampus (13). The naturally occurring low-n SDS-stable Aβ oligomers cause short term memory loss in rats, one of the earliest symptom associated with AD (19), and also affect dendritic morphology in neuronal cells resulting in synaptic losses (20). Concentration levels of this SDS-stable oligomeric form correlate strongly with dementia in AD patients (14). Unlike in vitro generated Aβ, naturally occurring low-n oligomeric aggregate does not dissociate in SDS (e.g., 1-10%) or chaotropic salts (e.g., 1-10%) such as guanidine hydrochloride, and cannot be pelleted from physiological fluids by ultra-centrifugation (15). The naturally occurring low-n oligomeric aggregates can be detected in brain tissue by Western blot analysis (16-17). They are also resistant to the Aβ degrading protease insulin degrading enzyme (IDE) (18).
These low-n SDS-stable oligomers cause short term memory loss in rats, one of the earliest symptom associated with AD (19), and also affect dendritic morphology in neuronal cells resulting in synaptic losses (20). While intracerebral injections of synthetic Aβ oligomers exerted a deleterious effect on learned behavior in rats (21-22), these responses were delayed and the concentrations and amounts of synthetic Aβ were much higher than concentrations of naturally derived SDS-stable low-n Aβ oligomers required to interfere with the memory of a complex learned behavior (19). Together these studies clearly suggest that the naturally derived SDS-stable Aβ oligomers may be important mediators in synaptic dysfunction in early AD and that these naturally derived oligomers behave differently than in vitro derived oligomers.
Passive immunization of various models of Alzheimer's Disease using antibodies against specific forms of conformational epitopes of Aβ structures has been suggested to improve cognitive functions in such models. However, when immunization was attempted with a mixture of Aβ peptide and adjuvant, it was found to produce autoimmune encephalitis. It was speculated that this adverse effect was due to the presence of polysorbate 80 in the final composition. Thus, the idea of immunization against Alzheimer's disease remains compelling but to date no immunization therapy has been effective against this disease.
Accordingly, there exists the need for new therapies and reagents for the treatment of Alzheimer's disease, in particular, therapies and reagents capable of effecting a therapeutic and diagnostic benefit at physiologic (e.g., non-toxic) doses.